This study assessed the effects of rifapentine or rifampicin on the pharmacokinetics of a single dose of bedaquiline and its “M2” metabolite in healthy subjects using a two-period single-sequence design. In Period 1, subjects received a single dose of bedaquiline (400 mg) followed by a 28-day washout. In Period 2, subjects received either rifapentine (600 mg) or rifampicin (600 mg) from Day 20 to Day 41 as well as a single bedaquiline dose (400 mg) on Day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 hours after administration of bedaquiline alone and in combination with steady-state rifapentine or rifampicin. Co-administration of bedaquiline with rifapentine or rifampicin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) for the bedaquiline Cmax, AUC(0-t), and AUC(0-inf) were 62.19% [90% CI (53.37-72.47)], 42.79% [90% CI (37.77-48.49)], and 44.52% [90% CI (40.12-49.39)], respectively, when coadministered with rifapentine. Similarly, the GMRs for the bedaquiline Cmax, AUC(0-t), and AUC(0-inf) were 60.24% [90% CI (51.96-69.84)], 41.36% [90% CI (37.70-45.36)], and 47.32% [90% CI (41.49-53.97)], respectively, when co-administered with rifampicin. The Cmax, AUC(0-t), and AUC(0-inf) of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampicin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampicin, were well tolerated with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampicin and other rifamycins. Strong CYP3A4 inducers should be avoided when considering the use of bedaquiline.
Winter, H.; Egizi, E.; Murray, S.; Erondu, N.; Ginsberg, A.; Rouse, D.J.; Severynse-Stevens, D.; Pauli, E. Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects. Antimicrobial Agents and Chemotherapy (2015) 59 (2) 1219-1224. [DOI: 10.1128/AAC.04171-14]